Increased expression of the Abcg2 transporter during erythroid maturation plays a role in decreasing cellular protoporphyrin IX levels
Increased expression of the Abcg2 transporter during erythroid maturation plays a role in decreasing cellular protoporphyrin IX levels
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DOI：
10.1182/blood-2004-04-1566
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发表时间：
2005-03-15
期刊：
影响因子：
20.3
通讯作者：
Sorrentino, BP
中科院分区：
文献类型：
--
作者：
Zhou, S;Zong, Y;Sorrentino, BP
ABCG2/BCRP是三磷酸腺苷结合盒（ABC）转运蛋白家族的成员，在肠、肾和肝脏中表达，并调节吸收。和外源化合物的排泄，ABCG2也在造血干细胞和红细胞中表达；然而，对其在造血中的作用知之甚少。Abcg2缺失小鼠红细胞中原卟啉IX （PPIX）水平升高，但其机制仍不确定。我们发现Abcg2 mRNA的表达在分化的红细胞中上调，与其他红细胞特异性基因的表达增加一致。这种表达模式与成熟外周血红细胞膜上大量的ABCG2蛋白有关。表达ABCG2的红细胞细胞内PPIX水平显著降低，提示ABCG2对PPIX水平有调节作用。这种调节活性被一种特定的ABCG2抑制剂Ko143所消除，这意味着PPIX可能是转运体的直接底物。综上所述，我们的研究结果表明，在红细胞分化过程中，ABCG2在调节PPIX水平中发挥作用，并提示ABCG2在红细胞生成原生卟啉症中可能发挥遗传决定因素的作用。(c) 2005年由美国血液学会出版
ABCG2/BCRP is a member of the adenosine triphosphate-binding cassette (ABC) transporter family and is expressed in intestine, kidney, and liver, where it modulates the absorption. and excretion of xenobiotic compounds, ABCG2 is also expressed in hematopoietic stem cells and erythroid cells; however, little is known regarding its role in hematopoiesis. Abcg2 null mice have increased levels of protoporphyrin IX (PPIX) in erythroid cells, yet the mechanism for this remains uncertain. We have found that Abcg2 mRNA expression was up-regulated in differentiating erythroid cells, coinciding with increased expression of other erythroid-specific genes. This expression pattern was associated with significant amounts of ABCG2 protein on the membrane of mature peripheral blood erythrocytes. Erythroid cells engineered to express ABCG2 had significantly lower intracellular levels of PPIX, suggesting the modulation of PPIX level by ABCG2. This modulating activity was abrogated by treatment with a specific ABCG2 inhibitor, Ko143, implying that PPIX may be a direct substrate for the transporter. Taken together, our results demonstrate that ABCG2 plays a role in regulating PPIX levels during erythroid differentiation and suggest a potential role for ABCG2 as a genetic determinant in erythropoietic protoporphyria. (c) 2005 by The American Society of Hematology